Currently available antipsychotics effectively control positive symptoms (hallucinations, delusions), but persistent negative symptoms (withdrawal, apathy) and cognitive deficits are little affected and can be quite disabling in most patients with schizophrenia. Recently, a new class of orally-bioavailable molecule that specifically enhances AMPA-type glutamate receptor activity has been developed. AMPAKINES facilitate acquisition and retention of memory in rodents and humans, and synergistically interact with modern antipsychotics. We recently completed an exploratory safety trial of the AMPAKINE CX516 added to clozapine in 19 treatment-resistant patients. CX516 was well tolerated and produced consistent improvements in negative symptoms, attention, and memory. We now propose to conduct a larger, placebo-controlled trial of CX516 added to olanzapine in patients with schizophrenia. The primary hypothesis is that CX516 will improve negative symptoms, attention, and verbal memory. Secondary aims are: 1) to asses the safety and tolerability of CX516 compared to placebo in olanzapine-treated patients; 2) to assess CX516 effects on positive symptoms, anxiety, depressive symptoms, executive function, and verbal fluency; and 3) to assess effects on extrapyramidal symptoms, including parkinsonism, akathisia and tardive dyskinesia. Positive effects on clinical (negative, positive, extrapyramidal) and neuropsychological (cognition, memory, attention) symptoms in a larger trial will strongly suggest that AMPAKINES may be useful for treatment of schizophrenia. PROPOSED COMMERCIAL APPLICATION: This research may lead to the development of a new, improved class of antipsychotic drug for schizophrenia. These new drugs have the potential to treat the diverse symptoms of this complex disease.